N-heterocyclization of primary amines with dihalides using microreactors

Article abstract of DOI:10.1080/00397911.2011.561944

(Chemical Equation Presented) A practical, rapid, and efficient reaction using microreactors for the direct N-alkylation from aniline derivatives and alkyl dihalides has been achieved in the presence of aqueous potassium carbonate at an elevated temperature. This improved synthetic methodology provides a straightforward microfluid approach to the synthesis of a variety of N-aryl azacycloalkanes. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.561944

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N-Heterocyclization of Primary Amines
with Dihalides Using Microreactors
Hongjie He a , Qi Lin a , Xiaofeng Liu a , Yongtai Yang a , Yaming Zhou
a , Yu Jia a & Xiang Gao a
a Department of Chemistry, Fudan University, Shanghai, P.R. China
Accepted author version posted online: 02 Jan 2012.Version of
record first published: 29 May 2012.
To cite this article: Hongjie He , Qi Lin , Xiaofeng Liu , Yongtai Yang , Yaming Zhou , Yu Jia & Xiang
Gao (2012): N-Heterocyclization of Primary Amines with Dihalides Using Microreactors, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:17, 2512-2525
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Synthetic Communications1, 42: 2512–2525, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.561944
N-HETEROCYCLIZATION OF PRIMARY AMINES WITH
DIHALIDES USING MICROREACTORS
Hongjie He, Qi Lin, Xiaofeng Liu, Yongtai Yang,
Yaming Zhou, Yu Jia, and Xiang Gao
Department of Chemistry, Fudan University, Shanghai, P.R. China
GRAPHICAL ABSTRACT
Abstract A practical, rapid, and efficient reaction using microreactors for the direct
N-alkylation from aniline derivatives and alkyl dihalides has been achieved in the presence
of aqueous potassium carbonate at an elevated temperature. This improved synthetic
methodology provides a straightforward microfluid approach to the synthesis of a variety
of N-aryl azacycloalkanes.
Keywords Azacycloalkanes; continuous process; microreaction; N-alkylation
INTRODUCTION
Recently, the use of microreactors for organic reactions has drawn a lot of
attention.[1–3] The typical dimensions of microreactors are in the range of
10–500 mm. Because of this microstructure and high surface-area–to–volume ratio,
it has particularly excellent heat and mass transfer characteristics.[4] In such a reaction
system, almost every site has the same temperature, so the phenomenon of local
Received December 23, 2010.
Address correspondence to Yu Jia or Xiang Gao, Department of Chemistry, Fudan University, 220
Handan Road, Shanghai 200433, China. E-mail: gaoxiang@fundan.edu.cn
2512

N-HETEROCYCLIZATION OF PRIMARY AMINES
2513
overheating or local overcooling can be avoided. Compared with conventional
macroscale batch reactors, the microreactor has excellent features, such as fast mix-
ing, fast heat transfer, and short residence time. Such advantages would favorably
affect reaction processes, and therefore the outcome has greater selectivity, yield,
and product quality in many cases.
In addition, microflow reactors enable the precise control of reaction conditions
and therefore facilitate highly selective reactions that are difficult to achieve in
conventional reactors.
N-Aryl heterocycles are of great significance to life because their structural sub-
units exist in many natural products.[5] They are one of the most common structural
features occurring in biologically active compounds and are widely used throughout
the chemical industry as basic intermediates or additives for the preparation of phar-
maceuticals, herbicides, dyes, and many other compounds.[6] According to previous
literature reports, the N-aryl heterocycles are generally prepared via the reaction of
pyrrolidine with halogenated benzene in the presence of a base (KOH or t-BuOK),[7]
the alkylation of amines by alcohols or halides,[8] or via the coupling reactions using
expensive metal catalysts.[9] These reactions are carried out in traditional batch reac-
tors. It always requires a long time (more than 4 h), harsh reaction conditions, or
expensive metal catalysts.
Recently, these reactions were performed using microwave reactors, which give
a faster and more sustainable result.[10] However, it requires the use of specialized
microwave equipment, and it is not suitable for large-scale reactions because of
the limited penetration depth of microwave irradiation into absorbing media.
In this study, double alkylation of aniline derivatives with alkyl dihalides on a
mild basic condition was first explored using microreactors. A series of N-aryl
azacycloalkanes have been successfully obtained in good yields within several min-
utes, which is a convenient and feasible approach to the synthesis of these important
chemicals on a large scale.
RESULTS AND DISCUSSION
The alkylation reaction using an integrated flow microreactor system, as repre-
sented in Fig. 1, was first examined. To accurately control the ratio of the precursors,
three kinds of materials were injected separately by three pumps (P1, P2 and P3). The
two organic reactants, aniline and dihalide, were dissolved separately in a low-
toxicity organic solvent, ethanol, then injected and mixed in micromixer M1, and
mixed with potassium carbonate aqueous solution that was injected by P3. By
adjusting the liquid’s flow rate of P1, P2, and P3, respectively, the injection volume
of the reactants could be easily controlled. To provide a better reaction environment
in which the mixture can be rapidly heated in sealed vessels at temperatures far above
the boiling point of the solvent during the experimental procedure, a pressure valve
(V1) was used to control the pressure inside the microreactors.
Because this is a heterogeneous mixture reaction procedure, the solid precipi-
tation is easily formed, which can block the microchannel. Thus, an appropriate ratio
between water and organic solvent is required to generate a uniform solution con-
dition. A broad wide ratio was tested in our experiment, and we found that the ratio

2514
H. HE ET AL.
Figure 1. Microflow system consisting of three injection pumps (P1, P2, P3), two T-shaped micromixers
(M1, M2), and one peek microtube reactor (inner diameter u ¼ 0.5 mm, length L ¼ 200 cm). (Figure is
provided in color online.)
of 5=2 water=ethanol is the best condition for all the reactions. The mixed solution
was passed through microtube reactor immersed in an oil bath, and the product
was collected directly.
The reaction of aniline and 1,4-dibromobutane was picked out as a model reac-
tion (Scheme 1) to optimize the reaction conditions.
Firstly, the effect of the ratio of precursors on the yields of the product was
investigated (Table 1). At a fixed temperature of 120 ꢀC and a controlled pressure
of 75 psi in the micro-reactor, the reaction accomplished completely when the molar
ratio of the three precursors was set to be 1=3=3 (Aniline=Dihalide=K2CO3). With
further reducing the amount of potassium carbonate, CO2 gas was generated
(Scheme 2). Then excessive internal pressure caused by accumulation of the gas
can cause further problems of injection, which was detrimental to this reaction in
the manner of continuous flow reaction.
The effect of different residence time (10 s-5 min) was then explored through adjust-
ing the flow rate. Ethanol solutions of aniline (2.0 mmol, flow rate: 0.011–0.330 mL=min),
1,4-dibromobutane (6.0mmol, flow rate: 0.011-0.330mL=min), respectively, as well as
the aqueous solution of K2CO3 (6.0 mmol, flow rate: 0.055-1.650 mL=min), were respect-
ively injected into the micro-reactor in an order as illustrated in Figure 1. It has been
shown that residence time has a great influence on the reaction yields. With the increase
of the residence time, the reaction gradually approached a completion (Figure 2). After 5
minutes, the aniline was nearly undetectable, indicating the best residence time for this
certain reaction. The crude product was purified by column chromatography to give
the pure compound of 1-phenyl-pyrrolidine at 95% yield.
This double-alkylation reaction using micro-reactor was then found to be appli-
cable to a variety of aniline derivatives to furnish N-aryl azacycloalkanes in high
yields. All the reaction results, which were performed with the optimized conditions,
Scheme 1. Synthesis of 1-phenyl-pyrrolidine in a microreactor system.

N-HETEROCYCLIZATION OF PRIMARY AMINES
2515
Table 1. Effect of feed ratio on the reaction yield
Product
Mol equiv ratio (A=B=C)
Yield (%)
1.0=1.1=1.1
1.0=2.0=2.0
1.0=2.0=3.0
1.0=3.0=3.0
21
54
75
95
1.0=1.1=1.1
1.0=2.0=2.0
1.0=2.0=3.0
1.0=3.0=3.0
38
50
61
96
Scheme 2. Carbon dioxide gas would be produced when an insufficient amount of alkali was used.
Figure 2. Effect of residence time on the yield of the reaction of substrate aniline at fixed temperature and
pressure. The yield detected by HPLC; temperature: 20ꢀC; pressure: 75 psi.

2516
H. HE ET AL.
are listed in Table 2. It can obviously be concluded that electron-donating substitu-
ents on anilines are a benefit for this cyclization reaction, giving both better reaction
rate and yields (entries 2–6 and 11). The reaction was also feasible with halogen sub-
stituted anilines. However, because of the electron-withdrawing effects, a longer reac-
tion time (10 min) was needed for a completed reaction (entries 7–10). In addition,
steric hindrance also has a great impact on the reaction rate as shown by entry 10.
Based on these results, N-alkylation of five-membered rings can be easily
performed in the micoreactors with good yields, even with electron-withdrawing or
steric hindrance groups on anilines. These results greatly inspired us to further study
different membered rings, which are still a great challenge in traditional batch reaction
conditions within acceptable reaction time. With the same synthetic condition, the
Table 2. Microfluid reactions of azacycloalkanes (part 1)
Entry
1a
Primary amines
Products
Time (min)
5
Yield (%)
95
2a
5
90
3a
4a
5a
5
5
5
94
96
96
6b
7a
5
5
98
64
5
10
33
80
8a
5
10
57
91
9a
5
30
57
90
10a
10
15
11b
5
85
aThe amount of primary amines added was at 2-mmol scale.
bThe amount of primary amines added was at 1-mmol scale. Temperature: 120 ꢀC; Pressure: 75 psi;
Yields based on starting aniline derivatives.

N-HETEROCYCLIZATION OF PRIMARY AMINES
2517
Table 3. Microfluid-reactions of azacycloalkanes (part 2)
Entry
Primary amines
Dihalides
Products
Time (min)
Yields (%)
12
13
Br(CH2)5Br
Br(CH2)5Br
5
5
93
89
14
Br(CH2)5Br
5
60
15
16
Br(CH2)6Br
Br(CH2)3Br
5
5
87
30
six- and seven-membered rings also have been obtained in good yields (Table 3, entries
12–15), though the yield of four-membered rings is relatively poor because of the high
ring strain (entry 16). Compared with the results of traditional reactions, using
microreactors can give excellent yields of these products in only serveral minutes.
Scheme 3. N-Heterocyclization of the ester-substituted aniline derivatives.
Figure 3. Effect of residence time on the yield of the reaction of ester-substituted aniline. Temperature:
120ꢀC; pressure: 75 psi.

2518
H. HE ET AL.
These results inspired us to further study a more challenging N-alkylation
reaction, the cyclization of ester-substituted aniline. The N-alkylation reaction is
generally carried out in an alkaline environment, which will no doubt cause hydroly-
sis of ester group (Scheme 3). This reaction was first carried out in a traditional reac-
tor, and as expected, very poor yield of the ester-substituted product was obtained
(<10%). Though further increasing the amount of alkaline, based on these results,
will help cyclization, the hydrolysis reaction could also be promoted. Then the same
reaction was conducted in our microreactor. A plot of the yield against the residence
time for this substrate is shown in Fig. 3, indicating that the yield progressively
increased with the residence time during the initial stage of the reaction. After
5 min, the yield of the ester-substituted product reached up to 68%. However, with
the the reaction time further prolonged, the yield decreased continually because of
the hydrolysis of the ester group. This result can be explained by the special nature
of the microreactor, high efficiency of rapid heat and mass transfer in short time,
leading to the high selectivity of the final product. The experimental results showed
that the proposed method has good prospects in improving the reaction selectivity.
CONCLUSION
The N-heterocyclization of primary amines with benzylic dihalides has been
studied in a continuous-flow laboratory-scale microreactor for the first time. We have
developed a new synthetic method in a microreactor system to prepare an important
class of compounds, N-aryl azacycloalkanes, in an aqueous=ethanol medium. With
this method, a high level control of the reaction process was achieved easily because
of fast mixing and accurate residence time control. Compounds have been synthesized
at excellent yields within much shorter reaction time than traditional methods. In
addition, the shortened reaction time and greater reaction efficiency could improve
reaction selectivity of some reactions, which were difficult to complete through the
traditional methods.
EXPERIMENTAL
Fabrication of Microreactor System
The continuous-flow microreactor system used for our studies mainly consists
of five parts (as shown in Fig. 1): three injection pumps (P1, P2, P3), two T-shaped
micromixers (M1, M2), a microtube (500 mm in i.d.), a pressure valve (V1, 75 psi),
and collection devices. The T-shaped PEEK micromixers were purchased from the
Dikma Company (cat no. 90148, used as tubing fittings in the HPLC instrument).
The microtube between M2 and V1 is a 200-cm-long Peek pipe, and the length
between M1 and M2 is 5 cm.
Typical Procedure for the Preparation of Azacycloalkanes
Using Microreactors
All starting amines and alkyl halides were obtained from Aldrich Chemical
Company and were used as such. Aniline 2.0 mmol was dissolved in 1 mL of anhy-
drous ethanol, 6.0 mmol of dihalides in 1 mL of anhydrous ethanol, and 6.0 mmol

N-HETEROCYCLIZATION OF PRIMARY AMINES
2519
of potassium carbonate in 5 mL of distilled water. The microreactor was placed in a
silicone oil bath, operated at 120 ꢁ 5ꢀC and under 75-psi pressure for 5–15 min. After
the completion of the reaction, ethanol was removed by vacuum distillation, and the
residue was extracted with ethyl acetate. The organic layer was collected, and the sol-
vent was removed under reduced pressure. The crude product was subjected to flash
1
chromatography column (EtOAc=hexane, 1:10, v=v) to afford azacycloalkane. H
NMR and infrared (IR) data were consistent with those illustrated in the literature.
Experimental Data
1H NMR spectra was recorded on a Jeol ECA NMR spectrometer. The exact
masses of unknown compounds were obtained using electronspray ionization from a
quadruple time-of-flight (micro) high-resolution mass spectrometer.
1-Phenylpyrrolidine (1a)[7a]
The reaction of aniline (2.0 mmol, 0.187 g) and 1,4-dibromobutane (6.0 mmol,
1.295 g) was carried out as described earlier and produced 0.279 g (95%) of 1-phenyl-
1
pyrrolidine as a yellow oil. H NMR (400 MHz, CDCl3=TMS) d ppm: 7.34 (t, 2H,
J ¼ 7.5 Hz), 6.78 (d, 1H, J ¼ 7.3 Hz), 6.67 (d, 2H, J ¼ 8.0 Hz), 3.38 (t, 4H, J ¼ 5.5 Hz),
2.09 (t, 4H, J ¼ 4.6 Hz). IR (KBr) n (cmꢂ1): 3029, 2966, 2870, 2833, 1610, 1594, 1506,
1486, 1460, 1371, 1342, 1184, 1157, 1033, 992, 854, 746, 691.
1-o-Tolylpyrrolidine (2a)[11]
The reaction of o-toluidine (2.0 mmol, 0.214 g) and 1,4-dibromobutane (6.0 mmol,
1.295 g) was carried out as described earlier and produced 0.290 g (90%) of 1-o-tolyl-
1
pyrrolidine as a colorless oil. H NMR (400 MHz, CDCl3=TMS) d ppm: 7.25 (m,
2H), 7.11 (m, 1H), 6.83(m, 1H), 3.19–3.17 (m, 4H), 2.32 (s, 3H), 1.93-1.91 (m,
4H). IR (KBr) n (cmꢂ1): 3057, 2965, 2872, 2810, 1599, 1494, 1461, 1443, 1356,
1312, 1146, 1056, 955, 753, 717.
1-m-Tolylpyrrolidine (3a)[12]

2520
H. HE ET AL.
The reaction of m-toluidine (2.0 mmol, 0.214 g) and 1,4-dibromobutane
(6.0 mmol,1.295 g) was carried out as described earlier and produced 0.303 g (94%)
of 1-m-tolylpyrrolidine as a colorless oil. 1H NMR (400 MHz, CDCl3=TMS) d
ppm: 7.09–7.13 (m, 1H), 6.49–6.51 (m, 1H), 6.39–6.38 (m, 2H), 3.28–3.25 (m, 4H),
2.31 (s, 3H), 2.00–1.94 (m, 4H). IR (KBr) n (cmꢂ1): 3033, 2966, 2871, 2830, 1603,
1579, 1498, 1487, 1458, 1367, 1321, 1246, 1172, 1024, 989, 834, 764, 690.
1-p-Tolylpyrrolidine (4a)[8]
The reaction of p-toluidine (2.0 mmol, 0.214 g) and 1,4-dibromobutane (6.0 mmol,
1.295 g) was carried out as described earlier and produced 0.309 g (96%) of 1-p-tolyl-
1
pyrrolidine as a colorless oil. H NMR (400 MHz, CDCl3=TMS) d ppm: 7.04 (d,
J ¼ 8.3 Hz, 2 H), 6.49 (brs, 2 H), 3.25–3.22 (m, 4 H), 2.24 (s, 3H), 2.00–1.95 (m, 4
H). IR (KBr) n (cmꢂ1): 3015, 2965, 2939, 2859, 1622, 1564, 1523, 1487, 1367,
1343, 1260, 1187, 1159, 963, 801.
1-(2,4-Dimethylphenyl)pyrrolidine (5a)[13]
The reaction of 2,4-dimethylaniline (2.0 mmol, 0.242 g) and 1,4-dibromobutane
(6.0 mmol, 1.295 g) was carried out as described earlier and produced 0.337 g
1
(96%) of 1-(2,4-dimethylphenyl)pyrrolidine as a yellow oil. H NMR (400 MHz,
CDCl3=TMS) d ppm: 6.99 (d, J ¼ 7.5 Hz, 1H), 6.69–6.64 (m, 2H), 3.19–3.16 (m,
4H), 2.29 (s, 3H), 2.28 (s, 3H), 1.94–1.89 (m, 4H). IR (KBr) n (cmꢂ1): 3019, 2965,
2871, 2809, 1608, 1575, 1504, 1413, 1354, 1311, 1148, 1118, 1007, 881, 846, 799.
1-(4-Methoxyphenyl)pyrrolidine (6a)[8]
The reaction of 4-methoxyaniline (1.0 mmol, 0.123 g) and 1,4-dibromobutane
(3.0 mmol, 0.648 g) was carried out as described earlier and produced 0.174 g
(98%) of 1-(4-methoxyphenyl)pyrrolidine as a white solid. 1H NMR (400 MHz,
CDCl3=TMS) d ppm: 6.86 (d, J ¼ 9.0 Hz, 2H), 6.54 (d, J ¼ 9.0 Hz, 2H), 3.76 (s,
3H), 3.24 (t, J ¼ 6.5 Hz, 4H), 2.01–1.98 (m, 4H). IR (KBr) n (cmꢂ1): 3045, 2962,
2945, 2866, 2825, 1616, 1516, 1488, 1452, 1372, 1283, 1237, 1178, 1043, 964, 814,
742, 589, 526.

N-HETEROCYCLIZATION OF PRIMARY AMINES
2521
1-(2-Fluorophenyl)pyrrolidine (7a)[14]
The reaction of 2-fluoroaniline (2.0 mmol, 0.222 g) and 1,4-dibromobutane
(6.0 mmol, 1.295 g) was carried out as described earlier and produced 0.211 g
(64%) of 1-(2-fluorophenyl)pyrrolidine as a colorless oil. 1H NMR (400 MHz,
CDCl3=TMS) d ppm: 7.00–6.98 (m, 2H), 6.67–6.65 (m, 2H), 3.46–3.44 (t, 4H),
2.05–2.03 (m, 4H). IR (KBr) n (cmꢂ1): 3028, 2963, 2871, 1613, 1506, 1449, 1437,
1360, 1261, 1205, 1050, 959, 811, 743, 648.
1-(3-Bromophenyl)pyrrolidine (8a)[15]
The reaction of 3-bromoaniline (2.0 mmol, 0.344 g) and 1,4-dibromobutane
(6.0 mmol, 1.295 g) was carried out as described earlier and produced 0. 149 g
1
(33%) and 0.362 g (80%) of 1-(3-bromophenyl)pyrrolidine as a yellow oil. H NMR
(400 MHz, CDCl3=TMS) d ppm: 7.26 (m, 1H), 7.07–7.03 (m, 1H), 6.76–6.67 (m,
2H), 3.27-3.23 (t, 4H), 2.01–2.00 (m, 4H). IR (KBr) n (cmꢂ1): 3036, 2964, 2925,
2849, 1593, 1552, 1494, 1461, 1437, 1371, 1261, 1171, 1082, 983, 819, 756, 680.
1-(3-Chlorophenyl)pyrrolidine (9a)[16]
The reaction of 3-chloroaniline (2.0 mmol, 0.255 g) and 1,4-dibromobutane
(6.0 mmol, 1.295 g) was carried out as described earlier and produced 0.207 g (57%)
and 0.330 g (91%) of 1-(3-chlorophenyl)pyrrolidine as a yellow oil. 1H NMR
(400 MHz, CDCl3=TMS) d ppm: 7.25 (m, 1H), 7.12–7.08(m, 1H), 6.52–6.51 (m,
1H), 6.42 (m, 1H), 3.27–3.23 (t, 4H), 2.01–2.00 (m, 4H). IR (KBr) n (cmꢂ1): 3068,
2969, 2839, 1596, 1560, 1497, 1461, 1372, 1276, 1247, 1094, 991, 824, 799, 756, 680.
1-(4-Bromo-2-methylphenyl)pyrrolidine (10a)

2522
H. HE ET AL.
The reaction of 4-bromo-2-methylaniline (2.0 mmol, 0.372 g) and 1,4-dibromobutane
(6.0 mmol, 1.295 g) was carried out as described earlier and produced 0.144 g (30%),
0.274 g (57%), and 0.432 g (90%) of 1-(4-bromo-2-methylphenyl)pyrrolidine as a
1
colorless oil. H NMR (400 MHz, CDCl3=TMS) d ppm: 7.26 (d, 1H), 7.21–7.20
(m, 1H), 6.73–6.71 (m, 1H), 3.17–3.15 (m, 4H), 2.28 (s, 3H), 1.94–1.91 (m, 4H).
IR (KBr) n (cmꢂ1): 3019, 2965, 2871, 2816, 1587, 1483, 1394, 1354, 1315, 1190,
1150, 1107, 951, 873, 805, 753, 663. ESI-HRMS calcd. for C11H14BrN: (Mþ) requires
m=z: 242.0323; found m=z: 242.0365.
1-(4-Phenoxyphenyl)pyrrolidine (11a)
The reaction of 4-phenoxyaniline (1.0 mmol, 0.185 g) and 1,4-dibromobutane
(3.0 mmol, 0.648 g) was carried out as described earlier and produced 0.203 g (85%)
1
of 1-(4-phenoxyphenyl)pyrrolidine as a colorless oil. H NMR (400 MHz, CDCl3=
TMS) d ppm: 7.28–7.26 (m, 2H), 7.25 (m, 3H), 6.99–6.92 (m, 2H), 6.56–6.55 (m,
2H), 3.28 (m, 4H), 2.02 (m, 4H). IR (KBr) n (cmꢂ1): 3041, 2960, 2842, 1607, 1512,
1470, 1383, 1291, 1231, 1156, 1071, 962, 867, 827, 752, 692, 508. ESI-HRMS calcd.
for C16H17NO: (Mþ) requires m=z: 240.1344; found m=z: 240.1386.
1-Phenylpiperidine (1b)[6b]
The reaction of aniline (2.0 mmol, 0.187 g) and 1,5-dibromopentane (6.0 mmol,
1.380 g) was carried out as described earlier and produced 0.299 g (93%) of 1-phenyl-
1
piperidine as a yellow oil. H NMR (400 MHz CDCl3=TMS) d ppm: 7.24 (t, 2H,
J ¼ 7.4 Hz), 6.93 (d, 2H, J ¼ 7.8 Hz), 6.82 (t, 1H, J ¼ 7.3 Hz), 3.15 (t, 4H, J ¼ 6.7 Hz),
1.70 (m, 4H), 1.56 (t, 2H, J ¼ 4.8 Hz). IR (KBr) n (cmꢂ1): 3060, 2934, 2853, 2805,
1598, 1501, 1450, 1384, 1334, 1237, 1131, 1025, 993, 918, 859, 756, 692.
1-(4-Methoxyphenyl)piperidine (2b)[17]
The reaction of 4-methoxyaniline (1.0 mmol, 0.123 g) and 1,5-dibromopentane
(3.0 mmol, 0.690 g) was carried out as described earlier and produced 0.170 g

N-HETEROCYCLIZATION OF PRIMARY AMINES
2523
(89%) of 1-(4-methoxyphenyl)piperidine as a white powder.1H NMR (400 MHz,
CDCl3=TMS) d ppm: 6.93–6.90 (m, 2H), 6.84–6.81 (m, 2 H), 3.76 (s, 3 H),
3.03–3.01(m, 4 H), 1.74–1.70 (m, 4 H), 1.56–1.52 (m, 2 H); IR (KBr) n (cmꢂ1):
3045, 2894, 2852, 2802, 1511, 1453, 1383, 1293, 1243, 1181, 1121, 1042, 919, 861,
766, 700.
1-(3-Chlorophenyl)piperidine (3b)[13]
The reaction of 3-chloroaniline (2.0 mmol, 0.255 g) and 1,5-dibromopentane
(6.0 mmol, 1.380 g) was carried out as described earlier and produced 0.234 g
(60%) of 1-(3-chlorophenyl)piperidine as a yellow oil. 1H NMR (400 MHz,
CDCl3=TMS) d ppm: 7.10 (dd, J ¼ 8.0 Hz, 2H), 6.85 (dd, J ¼ 2.0 Hz, 1H),
6.76–6.72 (m, 1H), 3.15–3.10 (m, 4H), 1.68–1.64 (m, 4H), 1.55–1.53 (m, 2H). IR
(KBr) n (cmꢂ1): 3068, 2937, 2853, 2800, 1595, 1565, 1488, 1384, 1341, 1240, 1131,
1100, 1028, 988, 938, 866, 772, 683.
1-Phenylazepane (4b)[6b]
The reaction of aniline (2.0 mmol, 0.187 g) and 1,6-dibromohexane (6.0 mmol,
1.464 g) was carried out as described earlier and produced 0.305 g (87%) of 1-pheny-
1
lazepaneas a colorless oil. H NMR (400 MHz, CDCl3=TMS) d ppm: 7.21–7.18 (t,
2H), 6.69–6.68 (d, 2H), 6.62 (t, 1H), 3.46–3.43 (t, 4H), 1.78 (m, 4H), 1.55–1.53 (m,
4H). IR (KBr) n (cmꢂ1): 3005, 2936, 2857, 1597, 1505, 1460, 1437, 1353, 1247,
1217, 1032, 896, 728, 644.
1-Phenylazetidine (5b)[7b]
The reaction of aniline (2.0 mmol, 0.187 g) and 1,3-dibromopropane (6.0 mmol,
1.211 g) was carried out as described earlier and produced 0.079 g (30%) of 1-pheny-
lazetidine as a yellow oil. 1H NMR (400 MHz, CDCl3=TMS) d ppm: 7.21 (t, 2H), 6.72
(t, 1H), 6.46 (d, 3H), 3.85–3.91 (m, 4H), 2.37–2.33 (m, 2H). IR (KBr) n (cmꢂ1): 3041,
2999, 2913, 2846, 1601, 1505, 1346, 1236, 1175, 1117, 1040, 989, 868, 750, 692.

2524
H. HE ET AL.
Dimethyl 5-(Pyrrolidin-1-yl)isophthalate (c1)[18]
The reaction of dimethyl 5-aminoisophthalate (1.0 mmol, 0.209 g) and 1,4-dibromo-
butane (6.0 mmol,1.295 g) was carried out as described earlier and produced 0.179 g
(68%) of dimethyl 5-(pyrrolidin-1-yl)isophthalate as a white powder. 1H NMR
(400 MHz, CDCl3=TMS) d ppm: 7.95 (d, 1H), 7.38–7.37 (m, 2H), 3.93–3.92 (s,
6H), 3.37–3.35 (m, 4H), 2.06–2.03 (m, 4H). IR (KBr) n (cmꢂ1): 3044, 2950, 2844,
1717, 1600, 1474, 1439, 1384, 1315, 1276, 1228, 1187, 1135, 1057, 1033, 880, 752.
ACKNOWLEDGMENT
The authors thank the National Research Program of China (973 Program),
2007CB714504.
REFERENCES
1. (a) Geyer, K.; Codee, J. D. C.; Seeberger, P. H. Chem. Eur. J. 2006, 12, 8434–8442; (b)
Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem.
Rev. 2007, 107, 2300–2318; (c) Watts, P.; Haswell, S. J. Chem. Soc. Rev. 2005, 34, 235–246.
2. (a) Ehrfeld, W. Microreaction Technology; Springer: Berlin, 1998; (b) Ehrfeld, W.; Hessel,
V.; Lo¨we, H. Microreactors; Wiley-VCH: Weinheim, 2000; (c) Hessel, V.; Hardt, S.; Lo¨we,
H. Chemical Microprocess Engineering; Wiley-VCH: Weinheim, 2004; (d) Yoshida, J.
Flash Chemistry. In Fast Organic Synthesis in Microsystems; Wiley-Blackwell: Chichester,
UK, 2008; (e) Wirth, T. Microreactors in Organic Synthesis and Catalysis; Wiley-VCH:
Weinheim, 2008; (f) Hessel, V.; Renken, A.; Schouten, J. C.; Yoshida, J. Microprocess
Engineering; Wiley-Blackwell: Weinheim, 2009.
3. (a) Fukuyama, T.; Rahman, M. T.; Sato, M.; Ryu, I. Synlett 2008, 151–163; (b) Yoshida,
J.; Nagaki, A.; Yamada, T. Chem. Eur. J. 2008, 14, 7450–7459; (c) Geyer, K.; Gustafsson,
T.; Seeberger, P. H. Synlett 2009, 2382–2391; (d) Lin, W.; Wang, Y.; Wang, S.; Tseng, H.
Nano Today 2009, 4, 470–481; (e) Hartman, R. L.; Jensen, K. F. Lab Chip 2009, 9, 2495–
2507; (f) Illg, T.; Lob, P.; Hessel, V. Bio. Med. Chem. 2010, 18, 3707–3719; (g) Marrea, S.;
¨
Jensen, K. F. Chem. Soc. Rev. 2010, 39, 1183–1202.
4. (a) Iwasaki, T.; Yoshida, J. Macromolecules 2005, 38, 1159–1163; (b) Razzaq, T.; Kappe,
C. O. Chem. Asian J. 2010, 5, 1274–1289.
5. Katritzky, A. R. Chem. Rev. 2004, 104(5), 2777–2812.
6. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893–930.
7. Doherty, S.; Smyth, C.; Knight, J. PCT Int Appl 2009, WO2008GB01680 20080515.
8. (a) Hamid, M. H. S. A.; Allen, C. L.; Lamb, G. W.; Maxwell, A. C.; Maytum, H. C.;
Watson, A. J. A.; Williams, J. M. J. J. Am. Chem. Soc. 2009, 131, 1766–1774; (b) Singh,
C. B.; Kavala, V.; Samal, A. K.; Patel, B. K. Eur. J. Org. Chem. 2007, 1369–1377.

N-HETEROCYCLIZATION OF PRIMARY AMINES
2525
9. (a) Guo, D.; Huang, H.; Xu, J.; Jiang, H.; Liu, H. Org. Lett. 2008, 10(20), 4513–4516; (b)
Kubo, T.; Katoh, C.; Yamada, K.; Okano, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron
2008, 64(49), 11230–11236.
10. (a) Ju, Y.; Varma, R. S., Org. Lett. 2005, 7(12), 2409–2411; (b) Ju, Y.; Varma, R. S., J.
Org. Chem. 2006, 71, 135–141.
11. Manolikakes, G.; Gavryushin, A.; Knochel, P. J. Org. Chem. 2008, 73, 1429–1434.
12. Hollmann, D.; Ba¨hn, S.; Tillack, A.; Parton, R.; Altink, R.; Beller, M. Tetrahedron Lett.
2008, 49, 5472–5745.
13. Ahman, J.; Buchwald, S., Tetrahedron Lett. 1997, 38, 6363–6366.
14. Perez-Pariente, J.; Gomez-Hortiguela, L.; Arranz, M. Chem. Mater. 2004, 16, 3209–3211.
15. Larsen, S. B.; Bang-Andersen, B.; Johansen, T. N.; Jørgensen, M. Tetrahedron 2008, 64,
2938–2950.
16. Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2001, 42, 247–250.
17. Hatakeyama, T.; Yoshimoto, Y.; Ghorai, S. K.; Nakamura, M. Org. Lett. 2010, 12(7),
1516–1519.
18. Tomoharu, L.; Hideki, J.; Hideki, K.; Masayuki, N.; Kenji, N.; Jun, S.; Tadashi, S.;
Hitomi, W.; Takeru, Y.; Lihu, Y. PCT Int. Appl., 2008, WO 2008-US247 20080108.